Amidino-hydrazone derivatives

ABSTRACT

The invention relates to novel amidino-hydrazone derivatives of the general formula: ##STR1## in which the dotted lines mean one extra bond starting from the (guanidine-) carbon atom to one of the adjacent nitrogen atoms, and 
     A stands for methylene, ethylene, propylene or butylene, which groups may optionally be substituted with alkyl (1-4 C), 
     R stands for hydroxy, alkyl (1-4 C), alkylthio or alkoxy (1-4 C), halogen, trifluoromethyl, nitro, amino, hydroxymethyl, acyloxy or an alkylenedioxy group, 
     N is the number 0, 1, 2, 3 or 4, 
     R 1 , r 4  and R 5  represent hydrogen or alkyl (1-4 C), with the proviso that one of them is absent in view of the presence of the double bond, 
     R 2  and R 3  stand for hydrogen, alkyl (1-4 C), aralkyl, aryl, hydroxy or amino, with the proviso that 
     R 2  + r 3  together may also represent a saturated or unsaturated alkylene group with 2 or 3 carbon atoms, or 
     R 3  + r 4  together with the nitrogen atom may also stand for a heterocyclic five- or six-membered ring, 
     As well as the pharmaceutically acceptable acid addition salts thereof, having valuable, antihypertensive and antithrombosis activities.

The invention relates to novel amidino-hydrazone derivatives, toprocesses for the preparation of these compounds and to pharmaceuticalpreparations containing these novel amidino-hydrazone derivatives as theactive component.

It has been found that amidino-hydrazone derivatives of the generalformula: ##STR2## in which the dotted lines mean one extra bond startingfrom the (guanidine-) carbon atom to one of the adjacent nitrogen atoms,and

A stands for methylene, ethylene, propylene or butylene, which groupsmay optionally be substituted with alkyl (1-4 C),

R stands for hydroxy, alkyl (1-4 C), alkylthio or alkoxy (1-4 C),halogen, trifluoromethyl, nitro, amino, hydroxymethyl, acyloxy or analkylenedioxy group,

n is the number 0, 1, 2, 3, or 4,

R₁, r₄ and R₅ represent hydrogen or alkyl (1-4 C), with the proviso thatone of them is absent in view of the presence of the double bond,

R₂ and R₃ stand for hydrogen, alkyl (1-4 C), aralkyl, aryl, hydroxy oramino, with the proviso that

R₂ + r₃ together may also represent a saturated or unsaturated alkylenegroup with 2 or 3 carbon atoms, or

R₃ + r₄ together with the nitrogen atom may also stand for aheterocyclic five- or six-membered ring,

as well as the pharmaceutically acceptable acid addition salts thereof,are very valuable biologically active substances.

The compounds I have a very strong antihypertensive activity, especiallyin case of oral administration, which property can be applied for thenormalization of undesirably high blood pressures in renal, neurogenicor essential hypertension. Moreover the compounds I have biocide andanti-thrombosis activities, more in particular they inhibit theaggregation of blood platelets and accelerate the disaggregation ofaggregates of blood platelets already formed.

The compounds according to the general formula I can be synthesised in amanner usual for analogous compounds.

The most simple, direct and generally applicable way for the preparationof the compounds I, is the direct condensation of an amidino-hydrazinederivative of the general formula II: ##STR3## or an acid addition saltthereof, in which the dotted lines, R₁, R₂, R₃, R₄ and R₅ have themeanings mentioned before, with an oxo-containing compound of thegeneral formula: in which R, A and n have the meanings mentioned before.

The starting products III are well-known compounds to which belong forexample: 1-benzocyclobutenon, 1-indanon and α-tetralon.

The reaction conditions for this condensation reaction are the usualconditions for the preparation of hydrazones.

An indirect manner for the preparation of the compounds I is a synthesisin which the last step is a reaction of a compound with the generalformula IV: ##STR4## or an acid addition salt thereof, in which thedotted lines, R, R₁, R₂, R₅, A and n have the meanings mentioned before,X is oxygen or sulphur and R₀ a lower alkyl group preferably a methylgroup,

with an amine of the formula V: ##STR5## or an acid addition saltthereof, in which R₃ and R₄ have the aforesaid meanings with the provisothat R₃ may additionally stands for an aminoalkyl- or aminoalkenyl groupwith 2 or 3 carbon atoms, if R₂ in formula IV stands for hydrogen.

This reaction is carried out under the usual conditions for thepreparation of guanidines. If a diamine of formula V (R₃ is aminoalkylor aminoalkenyl) is used, a ringclosure is effected additionally besidesthe aforesaid substitution of the XR₀ moiety (in formula IV).

The latter ringclosure is preferably performed at an elevatedtemperature; in that case the ammonia formed during the reaction can beremoved more readily.

Amines according to the general formula V that can be used in theabove-mentioned synthesis are, for example: ammonia, methylamine,dimethylamine, diethylamine, isopropylamine, dibutylamine, pyrrole,pyrrolidine, pyrroline, piperidine, imidazol, morpholine,1,2-diamino-ethane, 1-amino-2-methylamino-ethane, hydrazine,hydroxylamine, etc.

The starting products IV are prepared in a conventional manner, forinstance by reacting the oxo compound III with an iso(thio)ureaderivative of the formula: ##STR6## in which the dotted lines, R₁, R₂,R₅, X and R₀ have the aforesaid meanings.

Another method for the preparation of the compounds I is starting from acompound of the general formula IV: ##STR7## in which R, R₁, A and nhave the meanings mentioned before.

This starting product VI can be prepared for example by reacting acompound of formula III with hydrazine or an alkylhydrazine.

In various manners the starting product VI may be converted into thefinal product according to formula I, for instance by

a. reacting VI with a cyanamide or carbodi-imide of the formula VII:##STR8## in which the dotted lines, R₃, R₄ and R₅ have the aforesaidmeanings, in a conventional manner for the preparation ofguanidino-derivatives, or

b. reacting VI with an iso-urea or isothio-urea derivative of theformula VIII: ##STR9## in which the dotted lines, R₂, R₃, R₄, R₅, X andR₀ have the aforesaid meanings, in a conventional manner for thepreparation of guanidino-derivatives.

The compounds of formula I are of alkaline nature; they can therefore,depending on the medium in which they are prepared, be obtained as freebase or as acid addition salt. The free base can also be prepared fromthe salt in the usual way, for example by reacting with a strong base orwith the aid of an ion-exchanger.

A pharmaceutically acceptable acid addition salt is obtained by reactingthe free base I with a suitable inorganic or organic acid, such ashydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid,acetic acid, propionic acid, glycollic acid, maleic acid, fumaric acid,malonic acid, succinic acid, tartaric acid, lactic acid, citric acid,ascorbic acid, salicylic acid, benzoic acid, etc.

Some compounds according to the invention have an asymmetric carbon,namely those compounds I, wherein A stands for an alkylene (1-4 C) groupwhich is substituted with a lower alkyl group. Besides the racemicmixture also separate optical enantiomers can be obtained in that case.

These optically active final products I, which also belong to thecompounds according to the invention may be prepared in a conventionalmanner by resolution of the racemic final product. It is preferable,however, to start the synthesis in that case from an optically activestarting product, for example in optically active compound according toformula III.

By an alkyl group used in the various definitions accompanying thegeneral formula I is meant a branched or linear alkyl group of 1-4carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert.butyl. The alkyl group in the alkylthio and alkoxy moieties used in thedefinition of R has the same meaning.

By an aryl group mentioned in the definition of R₂ or R₃ is preferablymeant a substituted or non-substituted phenyl group, such as phenyl,p-chlorophenyl, p-bromophenyl, 2,6-dichlorophenyl, p-methoxyphenyl,p-tolyl, o,p-dimethylphenyl, etc.

By an aralkyl group mentioned in the definition of R₂ or R₃ ispreferably meant a substituted (particularly a phenyl or halogensubstituted) or non-substituted phenylalkyl group, in which the alkylgroup is an aliphatic hydrocarbon with 1-6 carbon atoms, such as benzyl,phenylethyl, diphenylmethyl, p-chlorophenylethyl, phenylpropyl,phenylpropen-2-yl, phenylbutyl, etc. or a phenyl moiety fused to acyclo-aliphatic hydrocarbon with 5 to 8 carbon atoms, such as indanyl or2,2-dimethylindanyl.

By an acyloxy group mentioned in the definition of R is meant a groupderived from a lower aliphatic carboxylic acid with 1-4 carbon atoms,such as acetic acid, propionic acid, butyric acid. Preferably theacetoxy group is employed.

If n ≧ 2 the substituents (R) at the benzo ring may be the same ordifferent groups.

The compounds according to the invention can be administered orally,locally and parenterally, preferably in a daily dosage of between 0.001and 50 mg per kg body weight.

Being mixed with suitable carriers the compounds I can be compressedinto solid dosage units, such as pills, tablets or coated tablets; theycan also be processed into capsules. By means of suitable diluents thecompounds I can be processed into injection preparations in the form ofsolutions, suspensions or emulsions.

A pharmaceutical preparation for oral administration is to be preferred.

Very suitable compounds I that can be used in antihypertensivepreparations are the compounds of formula I in which the benzo ring isunsubstituted, particularly those of the indane- andbenzocyclobutene-series, and the 4- or 6-monosubstituted or4,6-disubstituted compounds I belonging to the benzocyclobutene series.

Very suitable compounds I that can be used for preventing or combattingthrombosis are the 4- or 7-monosubstituted- or 4,7-disubstitutedcompounds I belonging to the indane-series and the 4- or6-monosubstituted or 4,6-disubstituted compounds I, belonging to thebenzocyclobutene series, and more in particular those compounds Iwhereby R₂ and R₃ together represent a saturated or an unsaturatedalkylene group, particularly an ethylene group.

EXAMPLE I 4,6-dimethylbenzocyclobutenone-1-amidinohydrazone.HCl and .CH₃COOH

To 2.92 g of 4,6-dimethylbenzocyclobutenone-1 (J. Org. Chem. 31, 2244(1966)) dissolved in 25 ml of glacial acetic acid, 2.25 g ofaminoguanidine.HCl are added, whereafter the mixture is stirred for 4hours at room temperature. Then 25 ml of ether are added, and theprecipitate formed is filtered off and recrystallised from water.

Yield: 4.0 g; melting point 256°-258° C.

If the reagent aminoguanidine.bicarbonate is used instead ofaminoguanidine.HCl, the acetate instead of hydrochloric acid salt isobtained.

Melting point of the acetate: 213°-214° C.

EXAMPLE II 4,7-dimethylindanone-1-amidinohydrazone.HCl

To 4.0 g of 4,7-dimethylindanone-1 (J.A.C.S. 72, 3286 (1950)), dissolvedin 30 ml of glacial acetic acid, 2.8 g of amidinoguanidine.HCl areadded, whereafter the mixture is stirred for 48 hours at roomtemperature. Then 30 ml of ether are added after which the precipitateformed is filtered off and recrystallised from ethanol.

Yield: 5.0 g; melting point: 234°-235° C.

EXAMPLE III1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-methylguanidine.HCl

To 2.92 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 25 ml ofglacial acetic acid, 2.49 g of 1-methyl-2-aminoguanidine.HCl 1 areadded. After stirring for 4 hours at room temperature, 25 ml of etherare added. The precipitate formed is filtered off and recrystallisedfrom ethanol/acetic acid/ether.

Yield: 4.2 g; melting point: 226°-227° C.

EXAMPLE IV 4-chloro-7-methyl-indanone-1-amidinohydrazone.HCl

To 2.3 g of 4-chloro-7-methylindanone-1 (J. Org. Chem. 14, 480, (1949))dissolved in 125 ml of glacial acetic acid, 1.4 g of aminoguanidine.HClis added. After stirring the mixture for 48 hours at room temperature 15ml of ether are added after which the precipitate formed is filtered offand recrystallised from ethanol.

Yield: 1.7 g; melting point: 267°-268° C.

EXAMPLE V 2-(1-indanylidene-hydrazino)-imidazoline.HCl -imidazoline.HCl

To 5.3 g of indanone-1, dissolved in 40 ml of glacial acetic acid, 5.5 gof 2-hydrazino-2-imidazoline.HCl are added. After stirring the mixturefor 16 hours at room temperature, the precipitate is filtered off andrecrystallised from ethanol-ether.

Yield: 8.2 g; melting point: 261°-263° C.

In a corresponding manner the compounds2-(1-indanylidene-hydrazino)-imidazol.hydrochloride and2-(1-indanylidene-hydrazino)-pyrimidine.hydrochloride are prepared bycondensation of indanone-1 with 2-hydrazino-imidazol and2-hydrazino-pyrimidine respectively.

EXAMPLE VI 4-methyl-7-chloro-indanone-1-amidinohydrazone.HCl

To 2.7 g of 4-methyl-7-chloro-indanone-1 (J. Org. Chem. 14, 480, (1949))dissolved in 15 ml of glacial acetic acid, 1.5 g of aminoguanidine.HClis added. After stirring the mixture for 16 hours at room temperature,the precipitate is filtered off and recrystallised from 90% ethanol.

Yield: 1.5 g; melting point: >250° C.

In the same manner are prepared:

4-methyl-indanone-1-amidinohydrazone.HCl; melting point >300° C,

4-methyl-7-acetoxy-1-amidiohydrazone.HCl; melting point 233° C (dec.),

4-chloro-indanone-1-amidinohydrazone.HCl; melting point 292°-295° C(dec.),

7-methyl-indanone-1-amidinohydrazone.HCl; melting point 274° C (dec.),

5-methyl-indanone-1-amidinohydrazone.HC1; melting point >275° C,

6-methyl-indanone-1-amidinohydrazone.HCl; melting point >250° C,

4-methyl-7-hydroxy-indanone-1-amidinohydrazone.CH₃ COOH; melting point225°-227° C (dec.),

4,7-di-isopropyl-indanone-1-amidinohydrazone.HCl; melting point274°-277° C (dec.),

4-methyl-7-amino-indanone-1-amidinohydrazone.2 HCl; melting point >250°C.

EXAMPLE VII 2-[1-(3-methyl-indanylidene-hydrazino)]-imidazoline.HCl

To 5.8 g of 3-methyl-indanone-1 (J.A.C.S. 62, 3499 (1940)), dissolved in40 ml of glacial acetic acid, 5.5 g of 2-hydrazino-2-imidazoline.HCl areadded. After being stirred for 16 hours at room temperature, thereaction mixture is evaporated and the residue recrystallised fromethanol-ether.

Yield: 8.5 g; melting point: 255°-260° C.

EXAMPLE VIII 4,5,6,7-tetramethylindanone-1-amidinohydrazone (acetate andhydrochloride

To 3.3 g of 4,5,6,7-tetramethylindanone-1 (Ber. 97, 3461 (1964)),dissolved in 17 ml of glacial acetic acid, 1.9 g of aminoguanidine.HClis added. After stirring the mixture for 72 hours at room temperature,the precipitate is filtered off.

Yield: 4.4 g; melting point: 265°-270° C (HCl salt).

This HCl salt is converted into the free base and then reacted withacetic acid to obtain the acetate. Recrystallisation from methanolyields 1.8 g acetate salt, melting point 224°-225° C.

EXAMPLE IX 1-(1-indanylidene-amino)-2,3-dimethylquanidine.HCl

To 5.3 g of indanone-1, dissolved in 40 ml of glacial acetic acid, 5.5 gof 2-amino-1,3-dimethylguanidine.HCl are added. After stirring themixture for 16 hours at room temperature the precipitate is filtered offand recrystallised from ethanol.

Yield: 9.5 g; melting point: 259°-261° C.

In the same manner is prepared:1-[1-(4,7-dimethylindanylidene-amino)]-2,3-dimethylguanidine.HCl,melting point: 233°-235° C.

EXAMPLE X2-[1-(4,6-dimethylbenzocyclobutenylidene-hydrazino)]-imidazoline.HCl

To 4.7 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 40 ml ofglacial acetic acid, 4.4 g of 2-hydrazinoimidazoline.HCl are added.After stirring the mixture for 4 hours at room temperature, 40 ml ofether are added after which the precipitate formed is filtered off andrecrystallised from ethanol-ether.

Yield: 6.6 g; melting point: 265°-268° C. The compound contains 1 mol H₂O.

EXAMPLE XI1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-hydroxyquanidine.HBr

To 0.67 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 10 ml ofglacial acetic acid, 0.8 g of 1-amino-2-hydroxyquanidine.HBr is added.After stirring the reaction mixture for 16 hours at room temperature, 10ml of ether are added. The precipitate is filtered off andrecrystallised from ethanol-ether.

Yield: 0.7 g; melting point: 196°-197° C.

EXAMPLE XII 1-(1-indanylidene-amino)-2-methylquanidine.HCl

A. direct route

0.66 g of 1-indanone, dissolved in 5 ml of glacial acetic acid, is addedto 0.68 g of 1-methyl-2-aminoguanidine.HCl, whereafter the mixture isstirred for 20 hours at room temperature. Then 5 ml of ether are added,after which the precipitate formed is filtered off and recrystallisedfrom ethanol-ether.

Yield: 1.0 g; melting point: 265°-267° C.

B. indirect route

1. 1-(1-indanylidene-amino)2-methylisothiourea.HJ

To 5.28 g of 1-indanone, dissolved in 100 ml of ethanol, 9.32 g ofS-methylisothiosemicarbazide.HJ are added. After refluxing for 3 hoursthe mixture is cooled down and the precipitate is filtered off anddried.

Melting point: 222°-223° C; yield: 10.4 g.

2. 1-(1-indanylidene-amino)-2-methylquanidine.HCl

1.73 g of 1-indanylidene-amino-2-methylisothiourea. HJ, obtained in B.1.is dissolved in 3.2 ml of dimethylsulfoxide, whereafter 3.2 ml of 3.1 Nmethylamine solution in ethanol are added. The mixture is stirred for 72hours at room temperature and further for 16 hours at 40° C. Then thereaction mixture is evaporated to dryness and the residue recrystallisedfrom ethanol-ether.

Melting point of the HJ salt: 233°-235° C; yield: 1.3 g.

This HJ salt is converted into the HCl salt (via the free base).

Melting point: 264°-267° C; yield: 0.7 g.

EXAMPLE XIII

a. 4,6-dimethylbenzocyclobutenone-1-thiosemicarbazone

To 1.46 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 25 ml ofethanol, 0.91 g of thiosemicarbazide is added. After refluxing for 3hours the mixture is cooled down and the precipitate formed filtered offand dried.

Yield: 2.0 g; melting point: 230°-232° C.

b. 1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-ethylisothiourea.HBr

To 8.0 g of 4,6-dimethylbenzocyclobutenone-1-thiosemicarbizone,suspended in 35 ml of ethanol, 3.24 ml of ethylbromide are added. Afterrefluxing for 3 hours the mixture is cooled down and the precipitateformed filtered off and dried.

Yield: 6.2 g; melting point: 214°-216° C. The same product is alsoprepared in the following manner. To 2.92 g of4,6-dimethylbenzocyclobutenone-1, dissolved in 50 ml of ethanol 4.0 g ofS-ethylisothiosemicarbazide.HBr are added. After refluxing for 3 hoursthe mixture is cooled down and the precipitate formed filtered off anddried.

Yield: 5.3 g; melting point: 212°-214° C.

c. 1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-methylisothiourea.HJ

To 1.46 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 25 ml ofethanol, 2.33 g of S-methylisothiosemicarbazide.HJ are added, afterwhich the mixture is refluxed for 3 hours and then cooled to ambienttemperature. The precipitate formed is filtered off and recrystallisedfrom ethanol.

Melting point: 209°-210° C; yield: 1.9 g.

d. By reacting the compound obtained in b) or c) with various amines inthe manner described in example XII B.2., the following compounds areobtained:

1. by a reaction of "b" with ammonia and converting the compoundobtained into the HCl salt:4,6-dimethylbenzocyclobutenone-1-amidinohydrazone.HCl.

2. by a reaction of "c" with dimethylamine and conversion into the HClsalt:1-(4,6-dimethylbenzocyclobutenylidene-amino)-2,2-dimethylguanidine.HCl.

3. by reaction of "c" with methylamine and conversion into the HCl salt:1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-methylquanidine.HCl.

4. by reaction of "b" with hydroxylamine:1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-hydroxyguanidine.HBr.

5. by reaction of "b" with hydrazine:1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-aminoguanidine.HBr.

6. by reaction of "b" with morpholine:1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-(anhydrobis-β-hydroxyethyl)guanidine.HBr.

EXAMPLE XIV1-(4,6-dimethylbenzocyclobutenylidene-amino)-2-aminoguanidine.HBr.

To 1.46 g of 4,6-dimethylbenzocyclobutenone-1, dissolved in 12.5 ml ofglacial acetic acid, 1.7 g of 1,2-diaminoguanidine.HBr is added. Afterstirring for 48 hours at room temperature, the precipitate formed isfiltered off and dried.

Yield: 2.5 g; melting point: 236°-241° C.

EXAMPLE XV 3,4,5,6-tetramethyl-benzocyclobutenone-1-amidinohydrazone.CH₃ COOH

To 5.22 g of 3,4,5,6-tetramethyl-benzocyclobutenone-1 (J.O.C. 31, 2244(1966)), dissolved in 35 ml of glacial acetic acid, 4.08 g ofaminoguanidine.H₂ CO₃ are added. After stirring for 24 hours at roomtemperature 70 ml of ether are added after which the precipitate formedis filtered off and recrystallised from methanol.

Melting point: 222°-223° C; yield: 5.0 g.

EXAMPLE XVI 6-amino-indanone-1-amidinohydrazone.2 HCl

3.67 g of 6-amino-indanone-hydrochloride (J. Chem. Soc. 123, 1469(1923)) are suspended in 35 ml of glacial acetic acid, whereafter 2.21 gof aminoguanidine.HCl are added. The mixture is stirred for 24 hours atroom temperature after which 35 ml of ether are added. The precipitateformed is filtered off, resuspended in 50 ml of ethanol and stirredagain.

Then the precipitate is filtered off and dried.

Yield: 4.5 g; melting point: >280° C.

EXAMPLE XVII 6-nitro-indanone-1-amidinohydrazone.CH₃ COOH

To 5.31 g of 6-nitro-indanone (Chem. Ber. 102, 3656 (1969)), dissolvedin 40 ml of glacial acetic acid, 4.08 g of aminoguanidine.H₂ CO₃ areadded. After stirring for 24 hours at room temperature, the precipitateformed is filtered off and recrystallised from glacial acetic acid.

Melting point: 215°-217° C (decomp.); yield: 7.25 g.

EXAMPLE XVIII Indanone-1-amidinohydrazone.HNO₃

28.0 g of 1-indanone (J.A.C.S. 88, 2233, 1966) and 58.1 g ofaminoguanidine.HNO₃ are stirred for 20 hours at room temperature in 250ml of glacial acetic acid and then poured out into 500 ml of water. Thecrystals formed are filtered off and washed again with water. Afterdrying over P₂ O₅ in vacuo, 36 g of indanone-1-amidinohydrazone. nitrateare obtained.

Melting point: 275°-276° C.

EXAMPLE XIX 2-methylindanone-1-amidinohydrazone.HNO₃ (racemate)

6.5 g of racemic 2-methylindanone-1 (Bull. Soc. Chim. France 1952, 462)and 12.2 g of aminoguanidine.HNO₃ are stirred for 20 hours at roomtemperature in 175 ml of glacial acetic acid and then poured out into150 ml of water. The crystals formed are filtered off, washed again withwater and dried in vacuo over P₂ O₅.

Melting point: 232°-234° C; yield: 7.0 g.

EXAMPLE XX 3-methylindanone-1-amidinohydrazone-HNO₃ (racemate)

6.6 g of racemic 3-methylindanone-1 (J. Am. Chem. Soc. 62, 3499 (1940))and 13.7 g of aminoguanidine.HNO₃ are stirred in 20 ml of glacial aceticacid for 20 hours at room temperature and then poured out into 250 ml ofwater. The crystals are filtered off, washed again with water and driedin vacuo.

Melting point: 265° C; yield: 14 g.

EXAMPLE XXI (α-tetralone)-amidinohydrazone.HCl

7.3 g of α-tetralone (Org. Synth. 35, 95 (1955)) and 5.5 g of-amidinohydrazone.HCl are stirred in 50 ml of glacial acetic acid for 18hours at room temperature. Then the mixture is evaporated to dryness andthe resulting oil crystallised in ethanol-ether.

Melting point: 167°-169° C; yield: 9.5 g.

EXAMPLE XXII 3,3-dimethylindanone-1-amidinohydrazone.HCl

8.15 g of 3,3-dimethylindanone-1 (Bull. Soc. Chim. France 1947, 812) and5.6 g of aminoguanidine.HCl are stirred for 18 hours in 50 ml of glacialacetic acid at room temperature. Then the mixture is evaporated andcrystallised in ethanol-ether.

Melting point: 195°-197° C; yield: 9.3 g.

EXAMPLE XXIII 5,6-dimethoxyindanone-1-amidinohydrazone.HCl

2.5 g of 5,6-dimethoxyindanone-1 (Ber. 102, 3656 (1969)) and 1.4 g ofaminoguanidine.HCl are stirred for 18 hours in 30 ml of glacial aceticacid at room temperature. Then the mixture is diluted with 30 ml ofether and the crystals formed sucked off and dried.

Melting point: 198°-200° C; yield: 3.6 g.

In the same manner is prepared:5,6-methylenedioxyindanone-1-amidinohydrazone.HCl and5,6-di(methylmercapto) indanone-1-amidinohydrazone.HCl.

EXAMPLE XXIV

In a similar way as described for some5,6-di-substituted-indanone-1-amidinohydrazones in example XXIII, thefollowing 4,7-di-substituted-indanone-1-amidinohydrazone derivatives areprepared:

4,7-dimethoxy-indanone-1-amidinohydrazone acetate, melting point 208° C(dec.),

1-(4,7-dimethyl-1-indanylidene-amino)-2-diphenylmethylguanidine.HClmelting point 271°-273° C,

1-(4,7-dimethyl-1-indanylidene-amino)-2(2',6'-dichlorophenyl)-guanidine.HClmelting point >275° C,

1-(4,7-dimethyl-1-indanylidene-amino)-2(2',2'-dimethyl-1'-indanyl)-3-methyl-guanidine.HBr;melting point 223° C (dec.).

EXAMPLE XXV (-)-S-3-methylindanone-1-amidinohydrazone.HCl

4.9 g of (+)-S-3-methylindanone-1 (Acta Chem. Scand. 18, 1483 (1964) and3.7 g of aminoguanidine.HCl in 40 ml of glacial acetic acid are stirredfor 18 hours at room temperature. After evaporation to dryness theresidue is recrystallised from ethanol-ether, yielding 4.35 g of(-)-S-3-methylindanone-1-amidinohydrazone.HCl, melting point: 194°-196°C; [α]_(D) ²⁰ = -67.3° (c = 1.3; CH₃ OH).

EXAMPLE XXVI (+)-R-3-methylindanone-1-amidinohydrazone.HCl

1.5 g of (-)-R-3-methylindanone-1 (Acta Chem. Scand. 18, 1483 (1964))and 1.14 g of aminoguanidine.HCl in 15 ml of glacial acetic acid arestirred for 18 hours at room temperature. After evaporation to drynessthe residue is recrystallised from ethanol-ether, yielding 1.2 g of(+)-R-3-methylindanone-1-amidinohydrazone.HCl, melting point: 194°-196°C; [α]_(D) ²⁰ = +67.2° (c = 0.8; CH₃ OH).

EXAMPLE XXVII

A. 1-(1-indanylidene-amino)-1-methylguanidine.HCl

To 3.1 g of indanone-1-methylhydrazone, dissolved in 20 ml of ethanol,2.5 g of S-methyl-isothiourea hydrochloride are added. The reactionmixture is refluxed for 24 hours and then cooled down. Ether (40 ml) isadded, after which the precipitate formed is filtered off andrecrystallised from ethanol/ether.

Yield: 1.2 g; melting point: 215°-225° C.

B. starting from 3,3-dimethylindanone-1-hydrazone is obtained in thesame manner as described in A.:3,3-dimethylindanone-1-amidinohydrazone.HCl.

Melting point: 194°-197° C.

Starting from 6-aminoindanone-1-hydrazone is obtained6-amino-indanone-1-amidinohydrazone.HCl.

Melting point: >280° C.

Starting from indanone-1-hydrazone is obtained:indanone-1-amidinohydrazone.HCl (Example XVIII).

C. the same compound as prepared in A. is also obtained by stirring amixture of cyanamide and indanone-1-methylhydrazone.HCl in toluene for24 hours at a temperature of about 70° C. Melting point: 215°-220° C.

EXAMPLE XXVIII 4-hydroxy-indanone-1-amidinohydrazone.HCl

A mixture of 110 mg of 4-hydroxy-indanone-1 and 148 mg ofamino-guanidine.HCl is refluxed for 20 hours in absolute methanol andthen cooled down. The precipitate formed is filtered off.

Yield: 179 mg; decomposition point above 270° C.

Rf in butanol:acetic acid:water (4:1:1) = 0.54 on SiO₂.

EXAMPLE XXIX

In the same manner as described in Example V the following compounds areprepared:

2-[1-(4,7-dimethylindanylidene-hydrazino)]-imidazoline.HCl, meltingpoint >300° C

2-[1-(4,7-dimethoxyindanylidene-hydrazino)]-imidazoline. HCl, meltingpoint 255° C (dec.)

2-[1-(4,7-dimethylindanylidene-methylhydrazino)]-imidazoline.HCl,melting point 181°-182° C

2-[1-(7-methylindanylidene-hydrazino)]-imidazoline.HCl, meltingpoint >280° C

2-[1-(4-methyl-7-hydroxy-indanylidene-hydrazino)]-imidazoline.HCl,melting point 242°-244° C

2-[1-(4,7-dimethylindanylidene-methylhydrazino)]-N-methylimidazoline.HCl,melting point 210°-212° C

2-[1-(4,7-dimethylindanylidene-hydrazino)]-N-methylimidazoline.HCl,melting point 270° C (dec.)

2-[1-(4-methyl-7-chloro-indanylidene-hydrazino)]-imidazoline.HCl,melting point >250° C (dec.)

2-[1-(4-methyl-7-acetoxy-indanylidene-hydrazino)]-imidazoline.HCl,melting point 204° C (dec.)

2-[1-(4-methylindanylidene-hydrazino)]-imidazoline.HCl, meltingpoint >250° C

2-[1-(4-chloro-indanylidene-hydrazino)]-imidazoline.HCl, meltingpoint >250° C

2-[1-(5,6-dimethoxy-indanylidene-hydrazino)]-imidazoline. HCl, meltingpoint 265° C (dec.)

2-[1-(4,7-dimethylindanylidene-hydrazono)]-N,N'-dimethylimidazolidine.HCl(oil), Rf in butanol:acetic acid:water (4:1:1) = 0.50 on SiO₂.

If tautomerism is possible with regard to the position of the doublebond of the guanidine moiety of the compounds of general formula I, thisdouble bond might also be present in conjugated position with respect tothe double bond attached to the benzocycloalkylene group. In that casean alternative nomenclature can be used; for example the first compoundof Example XXIX may also be named:2-[1-(4,7-dimethylindanylidene-hydrazono)]-imidazolidine.HCl.

We claim:
 1. A compound selected from the group consisting of a compoundof the formula: ##STR10## and a pharmaceutically acceptable acidaddition salt thereof, in which the dotted lines signify one extra bondstarting from the (guanidine-) carbon atom to one of the adjacentnitrogen atoms, and whereinA is a member of the group consisting ofmethylene, ethylene propylene, and butylene, which groups may optionallybe substituted with alkyl having 1 to 4 carbon atoms; R is a member ofthe group consisting of hydroxy, alkyl having 1 to 4 carbon atoms,alkylthio having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms,halogen, trifluoromethyl, nitro, amino, hydroxymethyl, acyloxy derivedfrom a lower aliphatic carboxylic acid having 1 to 4 carbon atoms, andalkylenedioxy; n is the number 0, 1, 2, 3, or 4; R₁, r₄ and R₅ are eacha member of the group consisting of hydrogen and alkyl having 1 to 4carbon atoms, with the proviso that one member is absent in view of thepresence of the double bond; and R₂ and R₃ is each a member of the groupconsisting of hydrogen, alkyl having 1 to 4 carbon atoms, aralkyl, aryl,hydroxy and amino.
 2. A compound according to claim 1 in which A is amethylene group optionally substituted with alkyl having 1 to 4 carbonatoms.
 3. A compound according to claim 1 in which A is an ethylenegroup optionally substituted with alkyl having 1 to 4 carbon atoms.
 4. Acompound according to claim 1 in which the substituent R in thebenzo-ring is present in at least one of the positions 4, 6 and 7.